JP2007507518A - Method for producing N-amino substituted heterocyclic compound - Google Patents

Abstract

Improved methods for the preparation of N-amino nitrogen heterocyclic compounds are disclosed and claimed. In an embodiment of the invention, a compound of formula (VI) is prepared, starting from the corresponding indole derivative as a means of N-amination and subsequently forming a hydrazone by reaction with a keto compound in a single step . Further reduction of the hydrazone and subsequent coupling with the pyridine compound provides the compound of formula VI or a suitable salt thereof.
[Chemical 1]

Description

  The present invention relates to a method for N-amination of a series of nitrogen-containing heterocyclic compounds. More specifically, the present invention relates to an improved process for the production of N-amino-indoles by N-amination of indoles. The invention also relates to an improved process for the preparation of N- (n-propyl) -N- (3-fluoro-4-pyridinyl) -1H-3-methyl-indole-1-amine and products derived therefrom. .

  A variety of N-amino substituted nitrogen heterocyclic compounds have been used as intermediates in the preparation of various organic compounds, and this compound is primarily used in pharmaceutical applications, among other applications. The A very important class of nitrogen heterocyclic compounds are N-aminoindoles. N-amination of indole and other nitrogen heterocycles, such as carbazole and pyrrole, can be converted to indole in the presence of excess potassium hydroxide in a solvent such as dimethylformamide (DMF) (hydroxylamine-O-sulfonic acid ( It has been reported in the literature that it can typically be done by adding HOSA) in portions (see, eg, Somei, M .; Natsume, M. Tetrahedron Letters 1974, 461). Similar N-amination procedures for indoles are described, for example, in US Pat. No. 5,459,274, both of which are hereby incorporated by reference in their entirety.

  However, the above method has some limitations and is not advantageous for the production of some N-aminoindoles, especially for large scale and industrial synthesis of N-aminoindoles. For example, adding hygroscopic HOSA in portions as a solid causes problems and is impractical. Furthermore, this reaction must be carried out under heterogeneous conditions, which results in unacceptably low yields of product. In practice, the yield of this product is typically at a low level of about 40% and is often variable depending on the surface area and quality of the potassium hydroxide used and the stirring efficiency of the reaction medium. This process is therefore not suitable for scale-up operations. Most importantly, a large excess of base is generally used, thus necessitating undesired waste disposal problems and post-treatment of the product after neutralization, thus making this process uneconomical for industrial operations. Make things.

  It is also disclosed in the literature that N-amination of hexamethyleneimine can be performed using HOSA in the presence of aqueous solvents and inorganic bases (eg, incorporated herein by reference in its entirety). EP patent application 0 249 452). The inorganic bases disclosed in this document include alkali metal hydroxides and alkaline earth metal hydroxides. In particular, in this process, it is disclosed that N-amination can be performed by simultaneous feeding of an aqueous HOSA solution and an aqueous sodium hydroxide solution to an aqueous hexamethyleneimine solution. However, this process is also associated with all the disadvantages discussed hereinabove, and furthermore, this process is specific to hexamethyleneimine, which is a variety of other It is a stronger base than nitrogen heterocyclic compounds such as indole, carbazole, pyrrole and the like. Despite this, the reported product yields are very low. Accordingly, there is a need for an improved process for N-amination of nitrogen containing heterocyclic compounds.

  As noted above, the N-amino nitrogen heterocyclic compounds thus formed serve as useful intermediates for the formation of N-alkylamino nitrogen-containing compounds (eg, N-alkylaminoindoles). In general, N-alkylation of an amino group can be performed using an alkylating agent such as a haloalkane in the presence of a base. However, such alkylation reactions often result in significant amounts of by-products resulting from competing alkylation of the heterocycle and are therefore undesirable (see, eg, US Pat. No. 5,459,274). Furthermore, such alkylation processes also produce undesirable by-products such as alkali halides that need to be disposed of, making industrial scale-up operations unsuitable.

  Accordingly, it is an object of the present invention to provide a novel homogeneous process for the N-amination of various nitrogen heterocyclic compounds.

  It is a further object of the present invention to provide a process for N-amination of nitrogen heterocyclic compounds with organic bases, whereby N-amino-heterocyclic compounds are produced in high yield and purity. Is done.

  It is also an object of the present invention to provide a novel N-alkylation process that does not produce any by-products, thus providing high purity N-alkylamino heterocyclic compounds.

  Other objects and further scope of applicability of the present invention will become apparent from the following detailed description.

の化合物の製造方法が提供される。 It has now been found that N-amination of various nitrogen heterocyclic compounds can be carried out in homogeneous media using organic bases and organic solvents such as aprotic solvents. Thus, according to one aspect of the present invention, the following formula II:

A method for producing the compound is provided.

の化合物の溶液を、適切な有機溶媒中で調製する。
（ｄ）最後に工程（ｄ）において、工程（ａ）で調製された溶液及び工程（ｂ）で調製された溶液を、工程（ｃ）で調製され適切な反応容器に収容された溶液に適切な温度で同時にそして釣り合った量で（proportionally）添加し、高純度及び高収量で式（II）の化合物を得る。 The method of the present invention includes the following steps.
(A) In step (a), a hydroxylamine-O-sulfonic acid (HOSA) solution is prepared in a suitable organic solvent.
(B) In step (b), a suitable base solution is prepared in a suitable organic solvent.
(C) In step (c), the following formula I:

Are prepared in a suitable organic solvent.
(D) Finally, in step (d), the solution prepared in step (a) and the solution prepared in step (b) are suitable for the solution prepared in step (c) and contained in a suitable reaction vessel. At the same temperature and in proportionate additions, the compound of formula (II) is obtained in high purity and yield.

Where R is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or fluoroalkyl of formula C _n H _x F _y or fluoroalkoxy of formula OC _n H _x F _y Where n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1,
R ₁ and R ₂ are the same or different and each is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or a fluoroalkyl of formula C _n H _x F _y or formula OC _n H _x F _y independently selected from fluoroalkoxy, where n is an integer from 1 to 4;
x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1, or R ₁ and R ₂ are taken together with the carbon atom attached to them. C ₅ -C ₈ cyclic ring to form Te, and m is 1 or 2.

In another aspect of the present invention, there is also provided another method for the preparation of a compound of formula II as described herein. The method of this aspect of the invention includes the following steps. In step (a), a solution of hydroxylamine-O-sulfonic acid and a compound of formula I as described herein is prepared in a suitable organic solvent. In step (b), a suitable base solution is prepared in a suitable organic solvent. In step (c), the solution prepared in step (a) is contacted with the solution prepared in step (b) simultaneously and in a balanced amount at an appropriate reaction temperature to obtain the formula ( II) is obtained. Here, R, R ₁ , R ₂ and m are as defined above.

の化合物の製造方法がまた提供される。 In yet another aspect of the invention, the following formula IV:

Also provided is a process for preparing the compound.

  In this aspect of the invention, the method includes: A hydroxylamine-O-sulfonic acid solution in a suitable organic solvent and a suitable base solution in a suitable organic solvent are simultaneously added to a compound solution of formula I as described herein in a suitable organic solvent. Then in balanced amounts and added at the appropriate reaction temperature, the compound of formula (I) as described herein is contained in a suitable reaction vessel. This reaction provides a compound of formula (II) as described herein.

の化合物と同じ反応容器で反応させて、式（IV）の化合物を得る。式中、Ｒ、Ｒ₁、Ｒ₂及びｍは上記で定義された通りであり、そしてＲ₃及びＲ₄は同一又は異なっており、そして各々は、水素又はＣ₁〜Ｃ₄−アルキルから独立して選択される。 The resulting N-amino-indole compound (II) is then converted to the following formula (III):

To give a compound of formula (IV). In which R, R ₁ , R ₂ and m are as defined above, and R ₃ and R ₄ are the same or different and each is independently of hydrogen or C ₁ -C ₄ -alkyl. Is selected.

の化合物の製造方法がまた提供される。 Finally, in yet another aspect of the present invention, the following formula VI:

Also provided is a process for preparing the compound.

In this aspect of the invention, the method includes the following steps.
In step (a), a compound of formula (IV) as described herein is first prepared essentially according to the procedure of the above embodiment. That is, a suitable reaction of a hydroxylamine-O-sulfonic acid solution in a suitable organic solvent and a suitable base solution in a suitable organic solvent simultaneously and in a balanced amount with a compound solution of formula I in a suitable organic solvent. It is assumed that the compound of formula (I), added at temperature and as described herein, is contained in a suitable reaction vessel. This reaction yields a compound of formula (II) as described herein. The resulting N-amino-indole compound (II) is then reacted in the same reaction vessel as the compound of formula (III) to give the compound of formula (IV).

の化合物を得る。 In step (b) of this inventive process, the compound of formula (IV) is reacted with a suitable reducing agent to give the following formula (V):

To obtain a compound of

の化合物と塩酸の存在下で反応させて、式（VI）の化合物をその塩酸塩として得る。ここで式中、Ｒ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄及びｍは上記で記載される通りである。Ｒ₅は、水素、
ニトロ、アミノ、ハロゲン、Ｃ_1-4−アルキル、Ｃ_1-4−アルカノイルアミノ、フェニル−Ｃ_1-4アルカノイルアミノ、フェニルカルボニルアミノ、アルキルアミノ又はフェニル−Ｃ_1-4アルキルアミノであり、Ｘはハロゲンであり、ｎは１又は２であり、そしてｐは０又は１である。 Finally in step (c) of the process according to the invention, the compound of formula (V) is
):

To give the compound of formula (VI) as its hydrochloride salt. Wherein R, R ₁ , R ₂ , R ₃ , R ₄ and m are as described above. R ₅ is hydrogen,
Nitro, amino, halogen, C _1-4 -alkyl, C _1-4 -alkanoylamino, phenyl-C _1-4 alkanoylamino, phenylcarbonylamino, alkylamino or phenyl-C _1-4 alkylamino, where X is Halogen, n is 1 or 2, and p is 0 or 1.

In yet another aspect of the present invention, a compound of formula (IV) is similarly obtained, wherein the above substituents are as described herein, provided that R and R ₃ are hydrogen. In this case, R ₄ is not hydrogen or methyl.

The terms used in this specification have the following meanings.
The expression “C _1-4 -alkyl” as used herein includes methyl and ethyl groups, as well as linear or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. “C _1-4 -alkoxy”, “phenyl-C _1-4 -alkylamino”, “amino-C _1-4 -alkyl”, “C _1-4 -alkylamino”, “mono-C _1-4- ” “Alkylamino or di-C _1-4 -alkylamino”, “C _1-4 -alkyl”, “diphenyl-C _1-4 -alkyl”, “phenyl-C _1-4 -alkyl”, “phenylcarbonyl” Derived expressions such as “) -C _1-4 -alkyl” and “phenoxy-C _1-4 -alkyl” should be interpreted accordingly.

The expression “C _1-6 -alkanoyl” as used herein should have the same meaning as “C _1-6 -acyl”, which is also represented structurally as “R—CO—”. Where R is C _1-5 -alkyl as defined herein. Furthermore, “C _1-5 -alkylcarbonyl” shall mean the same as C _1-6 -acyl. Specifically, “C _1-6 -acyl” should mean formyl, acetyl or ethanoyl, propanoyl, n-butanoyl, and the like. Derivative expressions such as “C _1-4 -acyloxy”, “C _1-4 -acyloxyalkyl”, “C _1-6 -alkanoylamino”, “phenyl-C _1-6 -alkanoylamino” are to be interpreted accordingly. Should be.

As used herein, the expression “C _1-6 -perfluoroalkyl” means that all hydrogen atoms in the above alkyl groups are replaced with fluorine atoms. Illustrative examples include trifluoromethyl and pentafluoroethyl groups and straight or branched heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and tridecafluorohexyl groups. . The derivative expression “C _1-6 -perfluoroalkoxy” should be interpreted accordingly.

The expression “heteroaryl” as used herein includes all aromatic radicals containing known heteroatoms. Exemplary 5-membered heteroaryl radicals include furanyl, thienyl or thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, and the like. Exemplary 6-membered heteroaryl radicals include radicals such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. Examples of representative bicyclic heteroaryl radicals include radicals such as benzofuranyl, benzothiofuranyl, indolyl, quinolinyl, isoquinolinyl and the like.

  The expression “heterocycle” as used herein includes all known cyclic radicals containing heteroatoms. Representative 5-membered heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl and the like. Exemplary 6-membered heterocyclic radicals include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and the like. Various other heterocyclic radicals include, but are not limited to, aziridinyl, azepanyl, diazepanyl, diazabicyclo [2.2.1] hept-2-yl and triazocanyl.

  “Halogen” or “halo” means chloro, fluoro, bromo and iodo.

  “Patient” as used herein refers to warm-blooded animals such as rats, mice, dogs, cats, guinea pigs, and primates (eg, humans).

  The term “pharmaceutically acceptable salt” as used herein means that a salt of a compound of the invention can be used in the manufacture of a medicament. However, other salts may be useful in the preparation of the compounds of the invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts, which include, for example, pharmaceutically acceptable acids (eg, hydrochloric acid, hydrobromic acid, Sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2- Phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid). Acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed. Also, the salt thus formed can exist as either a monoacid salt or a diacid salt and can exist as a hydrated state or be substantially anhydrous. In addition, when the compound of the present invention possesses an acidic moiety, suitable pharmaceutically acceptable salts thereof include alkali metal salts (eg, sodium or potassium salts), alkaline earth metal salts (eg, calcium salts or magnesium). Salts) and salts formed with suitable organic ligands (eg quaternary ammonium salts).

  The expression “stereoisomer” is a general term used for all isomers of individual molecules that differ only in the orientation of their atoms in space. Typically, this includes enantiomers (enantiomers) that are normally formed due to at least one asymmetric center. Where the compounds of the present invention have two or more asymmetric centers, these may additionally exist as diastereoisomers and certain individual molecules may exist as geometric isomers (cis / trans). . Similarly, certain compounds of the invention may exist in a mixture of two or more structurally different forms (commonly known as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that all such isomers and any proportions of these mixtures are included within the scope of the present invention.

In a broad sense, the term “substituted” is intended to include all permissible substituents of organic compounds. In some specific embodiments as disclosed herein, the term “substituted” is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 perfluoroalkyl. , Phenyl, hydroxy, —CO ₂ H, ester, amide, C _{1 to} C ₆ alkoxy, C _{1 to} C ₆ thioalkyl, C _{1 to} C ₆ perfluoroalkoxy, —NH ₂ , Cl, Br, I, F, —NH It means substituted (substituted) with one or more substituents independently selected from the group consisting of -lower alkyl and -N (lower alkyl) ₂ . However, any of the other suitable substituents known to those skilled in the art can also be used in these embodiments.

  Thus, in accordance with the practice of one aspect of the invention, methods are provided for the preparation of various N-amino substituted heterocyclic compounds. Thus, in a broad aspect of the invention, any nitrogen heterocyclic compound of formula (IA) below may be used to prepare the corresponding N-amino-heterocyclic compound as shown in Scheme 1.

  Representative examples of monocyclic nitrogen heterocyclic compounds of formula (IA) that can be utilized in the process of the present invention include substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1, Examples include, but are not limited to, 2,4-triazole. Representative examples of bicyclic nitrogen heterocyclic compounds of formula (IA) that can be utilized in the method of the present invention include substituted or unsubstituted indoles, 4,5,6 or 7-aza-indoles, purines, Examples include, but are not limited to, indazole, 4,5,6 or 7-aza-indazole, benzimidazole, 4,7-diazaindole and various other isomeric diazaindoles. Representative examples of tricyclic nitrogen heterocyclic compounds of formula (IA) that can be utilized in the method of the present invention include substituted or unsubstituted carbazoles or carbazoles substituted with various known heteroatoms. However, it is not limited to these. As defined herein above, any of the possible substituents are used in the case of the above substituted heterocyclic compounds provided that such substituents do not interfere with the process of the invention. obtain.

の化合物の製造方法が提供される。 Thus, in a particular embodiment of the invention, the following formula II:

A method for producing the compound is provided.

の化合物の溶液を、適切な有機溶媒中で調製する。 The method of this aspect of the invention includes the following steps.
(A) In step (a), a hydroxylamine-O-sulfonic acid (HOSA) solution is prepared in a suitable organic solvent.
(B) In step (b), a suitable base solution is prepared in a suitable organic solvent.
(C) In step (c), the following formula I:

Are prepared in a suitable organic solvent.

  Finally, in step (d), the solution prepared in step (a) and the solution prepared in step (b) are stored in an appropriate reaction vessel at the appropriate temperature prepared in step (c). At the same time and in balanced amounts to obtain the compound of formula (II) in high purity and yield.

Wherein R is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or fluoroalkyl of formula C _n H _x F _y or fluoroalkoxy of formula OC _n H _x F _y Where n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1,
R ₁ and R ₂ are the same or different and each is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or a fluoroalkyl of formula C _n H _x F _y or formula OC _n H _x F _y independently selected from fluoroalkoxy, where n is an integer from 1 to 4;
x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1, or R ₁ and R ₂ are taken together with the carbon atom attached to them. C ₅ -C ₈ cyclic ring to form Te, and m is 1 or 2.

  The compound of formula (II) can be prepared using processes as described above, but need not necessarily be prepared in different reaction vessels, essentially using these steps in the same reaction vessel. It must be noted that it can be manufactured with. Also, the order in which the reactants are added can be changed by changing the order of the steps if necessary.

  In one aspect of the method of the present invention, any suitable organic solvent known to those skilled in the art can be utilized in steps (a) and (b) of the method of the present invention. Particular types of organic solvents that can be utilized include broadly polar aprotic solvents and various nonpolar aprotic solvents or mixtures thereof. As used herein, an aprotic organic solvent means one that is neither a proton donor nor a proton acceptor. In general, aprotic solvents are more suitable for steps (a) and (b) of the process according to the invention.

Representative examples of suitable aprotic solvents in the method of the present invention include N-methylpyrrolidinone (NMP), N, N-dimethylformamide (DMF), dimethylacetamide (
DMAc), dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), and the like, but are not limited thereto. Mixtures of any proportion of these solvents can also be utilized. Examples of nonpolar organic solvents include, but are not limited to, tetrahydrofuran (THF), n-hexane, n-heptane, petroleum ether, and the like. Various halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. can also be utilized. In addition, any polar and non-polar solvent combinations such as NMP / hexane, NMP / heptane, etc. may also be utilized.

As shown, the method of the present invention uses a base in step (b) of the method of the present invention. In general, any base that can cause the required action can be used in this step of the method of the invention. In this step, it is generally advantageous to use organic bases, in particular organic bases that are soluble in the solvent used. This reaction can therefore be carried out in a homogeneous manner. Furthermore, the base having at least substantially the same pK _a value and pK _a values of indole is more suitable in this step of the process of the present invention.

  Suitable organic bases for this step include alkali metal alkoxides. Examples of suitable alkali metal alkoxides include lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, Examples thereof include, but are not limited to, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide, cesium tert-butoxide and the like. Mixtures of organic bases can also be utilized. Potassium tert-butoxide has been found to be a particularly suitable alkali metal alkoxide for carrying out the process of the invention.

  In step (c) of the process according to the invention, the solvent used is also an aprotic solvent. Any of the aprotic solvents listed above can be used in this step of the process of the invention. The same solvent as used in steps (a) and (b) can be utilized in this step as well. For example, such aprotic solvents include, but are not limited to, NMP, DMF, DMAc, and / or mixtures thereof.

  Any reaction temperature that will result in the intended result can be utilized in the present process. Generally suitable reaction temperatures can range from sub-ambient temperature to ambient temperature. For example, reaction temperatures of about −5 ° C. to about 40 ° C. are suitable for carrying out the process of the present invention. Even more suitably, reaction temperatures of about 0 ° C. to about 25 ° C. may be utilized in the present process. One skilled in the art generally understands and recognizes that higher temperatures generally increase the reaction rate. Thus, in certain cases, temperatures above ambient temperature, i.e. higher than room temperature up to the reflux temperature of the solvent, can be utilized.

  In general, the process according to the invention is carried out with an excess of base. For example, the base can be present in an amount of about 1 mole to about 10 moles based on the compound of formula I. However, to carry out the method of the present invention, the base may be present in an amount of about 3 moles to about 6 moles based on the compound of formula I.

  Similarly, HOSA is present in excess compared to the compound of formula (I). In the process according to the invention, it is generally advantageous to use HOSA in excess of the molar excess. More advantageously, it has now been found that only about a 2 molar excess of HOSA is sufficient to provide optimal results by practice of the present invention.

  The step of contacting the reaction solution produced in steps (a) and (b) with the reactant solution from step (c) can be performed by any method known in the art. For example, such contact in step (d) can be performed in a continuous reactor where the reactants are fed continuously, or static mixing (eg, static mixing with limited residence time, or a loop system). It can be performed by means of combined static mixing) or by means of a microreactor, but is not limited thereto. Various known static mixers, continuous reactors and microreactors can be utilized for this purpose. The continuous reaction can be processed in a continuous manner or batchwise by methods known in the art.

  Contact in step (d) can also be carried out in a batch reactor. Any of the known reactors that produce the desired results can be utilized. For example, in a batch operation, the reaction solution from steps (a) and (b) is fed to a reactor such as a stirred tank reactor containing the reaction solution from step (c). Various modifications known to those skilled in the art can be used to effect the addition of these reaction solutions in this mode of operation.

As mentioned hereinabove, a variety of nitrogen heterocyclic compounds can be utilized in the method of the present invention. For example, compounds of formula (I) where R and R ₁ are hydrogen and R ₂ is methyl can be utilized in the method of the invention, but are not limited thereto. Preference is also given to compounds of the formula (I) in which R ₁ and R ₂ together with the carbon atoms bonded to them form a benzene ring. Specific examples of such compounds are as described herein above. For example, substituted or unsubstituted carbazole can be utilized.

In another aspect of the present invention, there is also provided another method for the preparation of a compound of formula II as described herein. The method of this aspect of the invention includes the following steps. In step (a), a solution of hydroxylamine-O-sulfonic acid and a compound of formula I as described herein is prepared in a suitable organic solvent. In step (b), a suitable base solution is prepared in a suitable organic solvent. In step (c), the solution prepared in step (a) is contacted at the appropriate reaction temperature in a simultaneous and balanced amount with the solution prepared in step (b) to obtain a high purity and high yield formula. A compound of (II) is obtained. In which R, R ₁ , R ₂ and m are as defined above.

  Again, as before, the above method of the present invention can be carried out using any of the reactors known in the art. For example, a stirred tank reactor, a continuous reactor, a microreactor or a static mixer can be used, but is not limited thereto. The above process of the present invention is particularly suitable for carrying out amination reactions in a continuous stirred tank reactor.

  In this embodiment of the invention, any solvent suitable for carrying out this reaction may be utilized. More preferably, all solvents as described herein above may also be utilized in this embodiment. In general, aprotic solvents such as those described herein, such as NMP, DMF, or DMAc are more preferred solvents.

  In this embodiment, the base used is a base that will give the intended result. Any of the known bases can be utilized. More preferably, however, bases such as organic bases as described above may be used in this embodiment of the invention. In general, it is more preferred to use an organic base that is soluble in the reaction solvent utilized as described herein above. Particular examples of organic bases suitable for this embodiment include alkali metal alkoxides such as potassium tert-butoxide.

  It will also be recognized by those skilled in the art that any reaction temperature that will result in the intended result can be utilized in this embodiment of the process of the invention. Again as described herein above, generally sub-ambient to ambient temperatures are suitable for performing the method of the present invention. However, in certain situations, temperatures above ambient can also be utilized.

  Furthermore, it is generally advantageous to carry out the process according to the invention using an excess of base as well as HOSA when compared to the compounds of formula (I). More advantageously, as noted above, even in this embodiment, only about a 2 molar excess of HOSA is sufficient to provide optimal results. Similarly, a base excess of about 1 mole to about 10 moles may be utilized, but the base is present in an amount of about 3 moles to about 6 moles based on the compound of formula I as described herein above. obtain.

の化合物の製造のための方法がまた提供される。 In yet another aspect of the invention, the following formula IV:

Also provided are methods for the preparation of the compounds.

  In this aspect of the invention, the method includes: A hydroxylamine-O-sulfonic acid solution in a suitable organic solvent and a suitable base solution in a suitable organic solvent are simultaneously added to a compound solution of formula I as described herein in a suitable organic solvent. At the appropriate reaction temperature, and as described herein, the compound of formula (I) is contained in a suitable reaction vessel as described above. . This reaction results in a compound of formula (II) as described herein.

の化合物と同じ反応容器中で反応させて、式（IV）の化合物を得る。式中、Ｒ、Ｒ₁、Ｒ₂及びｍは上記で定義された通りであり、そしてＲ₃及びＲ₄は同一又は異なっており、そして各々は、水素又はＣ₁〜Ｃ₄−アルキルから独立して選択される。 The resulting N-amino-indole compound (II) is then converted to the following formula (III):

To obtain a compound of formula (IV). In which R, R ₁ , R ₂ and m are as defined above, and R ₃ and R ₄ are the same or different and each is independently of hydrogen or C ₁ -C ₄ -alkyl. Is selected.

  In this embodiment of the invention, the amination of the compound of formula (I) to the compound of formula (II) is carried out using essentially similar procedures as described above in the other two embodiments of the invention. Done. Thus, all of the solvents, bases and reaction vessels described above can be used in this embodiment. Similarly, the same reaction conditions as described above can be utilized. In general, an aprotic solvent such as NMP, DMF or DMAc and an organic base such as potassium tert-butoxide together with HOSA can be utilized at temperatures ranging from about −5 ° C. to about 40 ° C. A temperature in the range of about 0 ° C. to about 25 ° C. is particularly preferred.

  Furthermore, as indicated above, it is generally advantageous to carry out the process of the invention with an excess of base and HOSA when compared to the compound of formula (I). More advantageously, even in this embodiment as described above, only about a 2 molar excess of HOSA is sufficient to provide optimal results. Similarly, a base excess of about 1 mole to about 10 moles can be utilized, but the base can be present as described above in an amount of about 3 moles to about 6 moles based on the compound of formula I.

  Advantageously, it has now been found that the reaction of a compound of formula (II) with a compound of formula (III) can be carried out in the same reaction vessel by addition of a compound of formula (III). In general, the compound of formula (III) may be added alone after formation of the compound of formula (II). However, it may be advantageous to add some organic or inorganic acid. Suitable organic acids include acetic acid, propionic acid, n-butyric acid and the like. It has also been found beneficial to use water with organic acids. Suitable inorganic acids include hydrochloric acid, nitric acid, sulfuric acid and the like. Generally, the acid is added in an amount such that the reaction medium is maintained at a pH of about 4.

This addition reaction may generally be carried out at ambient temperature, but sub-ambient to ambient temperatures may also be used depending on the type of compound of formula (II) and the type of compound of formula (III) used. obtain. Generally, temperatures in the range of about 0 ° C. to about 100 ° C. can be used. A temperature in the range of about 5 ° C to about 30 ° C is preferred. In particular, an ambient temperature of about 20 ° C. is preferred.

Various compounds of formula (III) may be used in the method of the present invention. Examples of such compounds include, but are not limited to, various known aldehydes and ketones. Specific examples of aldehydes include, but are not limited to, formaldehyde, acetaldehyde, propionaldehyde, n-butyraldehyde, iso-butyraldehyde, benzaldehyde, phenylacetaldehyde, and the like. Suitable ketones for this method include, but are not limited to, acetone, methyl ethyl ketone, diethyl ketone, acetophenone, benzophenone, and the like. In general, aldehydes are the more preferred reactants in the process of the present invention, and propionaldehyde is the most preferred compound of formula (III).

In a further aspect of the invention, embodiments of the invention include products produced according to the method of the invention. Specifically, the product produced according to the process of the present invention is such that R, R ₁ and R ₄ are hydrogen, R ₂ is methyl, and R ₃ is ethyl. More specifically, the product produced according to the process of the present invention is 3-methyl-N- (propylidene) -1H-indole-1-amine.

の化合物の製造のための方法がまた提供される。 Finally, in yet another aspect of the invention, the following formula VI:

Also provided are methods for the preparation of the compounds.

In this aspect of the invention, the method includes the following steps.
In step (a) of this embodiment of the method of the invention, a compound of formula (IV) as described herein is first prepared essentially according to the procedure of the embodiment described above. That is, a suitable solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent in a suitable amount simultaneously and in proportion to a solution of the compound of formula I in a suitable organic solvent. Although added at the reaction temperature, the compound of formula (I) should be contained in a suitable reaction vessel as described herein. This reaction provides a compound of formula (II) as described herein.

  The resulting N-amino-indole compound (II) is then reacted in the same reaction vessel as the compound of formula (III) to provide the compound of formula (IV).

の化合物を得る。 In step (b) of the process according to the invention, the compound of formula (IV) is reacted with a suitable reducing agent to give the following formula (V):

To obtain a compound of

の化合物と適切な有機溶媒中の適切な塩基の存在下で反応させて、式（VI）の化合物を提供する。式（VI）の化合物を、場合により無機酸、例えば塩酸と処理して、式（VI）の化合物の塩、例えば塩酸塩を得る。式中、Ｒ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄及びｍは上記で記載される通りである。Ｒ₅は、水素、ニトロ、アミノ、ハロゲン、Ｃ_1-4−アルキル、Ｃ_1-4−アルカノイルアミノ、フェニル−Ｃ_1-4−アルカノイルアミノ、フェニルカルボニルアミノ、アルキルアミノ又はフェニル−Ｃ_1-4−アルキルアミノであり、Ｘはハロゲンであり、ｎは１又は２であり、そしてｐは０又は１である。 Finally, in step (c) of the method of the present invention, the compound of formula (V) is then converted to the following formula (VII):

Is reacted with a compound of formula (VI) in the presence of a suitable base in a suitable organic solvent to provide a compound of formula (VI). The compound of formula (VI) is optionally treated with an inorganic acid such as hydrochloric acid to give a salt of the compound of formula (VI) such as the hydrochloride salt. In which R, R ₁ , R ₂ , R ₃ , R ₄ and m are as described above. R ₅ is hydrogen, nitro, amino, halogen, C _1-4 -alkyl, C _1-4 -alkanoylamino, phenyl-C _1-4 -alkanoylamino, phenylcarbonylamino, alkylamino or phenyl-C _1-4 -Alkylamino, X is halogen, n is 1 or 2, and p is 0 or 1.

  Again, as before, it should be understood that the steps discussed hereinabove are for illustrative purposes only. The order in which these steps are performed can be varied and / or one or more of these steps can be performed simultaneously and / or in parallel. Accordingly, various modifications of these processes also form part of the present invention. More advantageously, all these steps can be carried out in the same reaction vessel in a single batch operation or in a continuous reactor.

  Thus, according to this aspect of the invention, in step (a) of this embodiment, the amination of the compound of formula (I) to form the compound of formula (II) may be carried out by using a solvent, preferably an aprotic solvent, a base. This is carried out essentially in the same manner as described above, preferably by using the organic base and HOSA at a temperature below about ambient to the ambient reaction temperature.

The compound of formula (II) thus formed is then converted to the compound of formula (IV) by reacting with the compound of formula (III) as described above, generally in the same reaction vessel. Reaction conditions and suitable compounds of formula (III) are the same as those described above.

  As described above, the compound of formula (IV) is then reduced to the compound of formula (V). This reduction reaction can be performed using any of the procedures known in the art. In general, this reduction can be performed using any of the known C═N reducing agents (eg, Schiff bases, hydrazones or reducing agents typically used for the reduction of imines). Examples of suitable reducing agents include lithium aluminum hydride, sodium borohydride, sodium borohydride and glacial acetic acid, sodium acetoxyborohydride, sodium diacetoxyborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium -Ethanol, hydrogen, catalyst and the like are included, but are not limited thereto.

Other reducing agents such as dibutyltin hydrochloride (Bu ₂ SnClH) in HMPA can also be utilized. Various boron reagents can also be utilized. Specific examples include diborane, boron-sulfide complexes such as boron-dimethyl sulfide or boron-1,4-thioxan complexes; boron etherates such as boron-THF complexes; boron-amine complexes such as boron-ammonia, boron-tert. -Butylamine, boron-N-ethyl-diisopropylamine, boron-N-ethylmorpholine, boron-N-methylmorpholine, boron-morpholine, boron-piperidine, boron-pyridine, boron-triethylamine and boron-trimethylamine; boron-phosphine complex Boron-tributylphosphine or boron-triphenylphosphine: boron hydride mixtures such as sodium borohydride and tetra-alkylammonium borohydrides; Reagents that produce hydrogen, such as a combination of sodium borohydride and iodine, a combination of sodium borohydride and BF ₃ -dietherate, a combination of sodium borohydride and chlorotrimethylsilane, a tetra-alkylammonium borohydride and an alkyl bromide, such as a combination of n-butyl bromide; and the like. It has now been found that sodium borohydride in the presence of glacial acetic acid is generally a more preferred reducing agent in this step of the process of the invention.

  This reduction reaction is also carried out in the presence of a suitable organic solvent. Typically, aprotic polar solvents, such as those described herein, are more suitable for performing the reduction step. Specific examples of such organic solvents include, but are not limited to, NMP, DMF, DMAc, THF, heptane, hexane, toluene, petroleum ether, and the like.

  Surprisingly, it has now been found that polar aprotic solvents and mixtures of nonpolar solvents provide some advantage, especially in carrying out this reduction step. Specific examples of such mixtures of solvents include, but are not limited to, NMP / heptane, NMP / hexane, NMP / petroleum ether, DMF / hexane, DMF / n-heptane, and the like. In particular, it has now been found that a mixture of NMP and n-heptane provides a certain advantage in the method of the invention in that it significantly reduces reagent foaming.

  Reduction of a compound of formula (IV) to a compound of formula (V) can generally be performed at any temperature that will produce the desired result. Thus, temperatures below ambient temperature to ambient temperature and from ambient temperature to ambient temperature can be used depending on the type of compound and reagent utilized. In general, temperatures in the range of about 0 ° C. to about 60 ° C. are suitable. A temperature in the range of about 5 ° C to 40 ° C is typically used. A temperature of about 30 ° C is preferred.

  The compound of formula (V) can be further isolated as a suitable salt, for example the hydrochloride salt, by reaction with a suitable acid, for example hydrochloric acid. In general, the salt of the compound of formula (V) is a crystalline solid and therefore, if necessary, before conversion of this compound to the compound of formula (VI) in subsequent reactions with the compound of formula (VII) ) Is purified.

  The reaction of the compound of formula (V) can be carried out with various pyridine derivatives of formula (VII) to form a compound of formula (VI), wherein preferably X is Cl and p A compound of formula (VII) is used when is 0. Examples of such compounds of formula (VII) include 4-chloropyridine, 4-chloro-3-fluoro-pyridine, 4-chloro-2-fluoro-pyridine and 4-chloro-3,5-difluoro-pyridine. However, it is not limited to these.

  This reaction may be carried out using aprotic polar solvents such as those used in the previous process steps, such as but not limited to NMP, DMF, DMAc, THF, heptane, hexane, toluene, petroleum ether, etc. It is carried out in a mixture of an aprotic solvent and a nonpolar solvent, such as, but not limited to, NMP / heptane, NMP / hexane, NMP / petroleum ether, DMF / hexane, DMF / n-heptane and the like. A variety of other solvents can also be utilized in this step of the process of the invention. Examples of suitable solvents for this step include ethereal solvents such as bis (2-methoxyethyl) ether, diethyl ether, dimethoxy ether, dioxane or THF; polar aprotic solvents described herein. Such as DMF, DMAc, HMPA or DMSO; or protic solvents such as methanol, ethanol, isopropanol and the like. Also, as indicated above, any combination of mixtures of these solvents can also be used. Typically, this reaction is performed using the same solvent, such as NMP or a mixture of NMP and heptane.

  Suitable organic bases for this step include alkali metal alkoxides. Examples of suitable alkali metal alkoxides include lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, Potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide, cesium tert-butoxide, etc .; alkali metal hydrides such as sodium hydride or potassium hydride However, it is not limited to these. Mixtures of organic bases can also be used. Potassium tert-butoxide has been found to be a particularly suitable alkali metal alkoxide for carrying out this step of the process of the invention.

  The reaction of the compound of formula (V) with the pyridine derivative (VII) to form the compound of formula (VI) can generally be performed at any temperature that will produce the desired result. Thus, sub-ambient to ambient temperatures and ambient temperatures to ambient temperatures can be used depending on the type of compound and reagent used. In general, temperatures in the range of about 70 ° C to about 150 ° C are suitable.

  The compound of formula (VI) can be further reacted with a suitable inorganic acid to give a suitable salt of the compound of formula (VI). An example of such an inorganic acid is hydrochloric acid, resulting in the hydrochloride salt of the compound of formula (VI). In general, the salt of the compound of formula (VI) is a crystalline solid, thus providing a method for purifying the compound of formula (VI) if necessary before utilizing it, for example, for pharmaceutical purposes.

  This reaction can be carried out in the same reaction vessel or in different reaction vessels after isolation of the compound of formula (V) as indicated above. The above method of the invention can be carried out using any of the reactors known in the art. Again, stirred tank reactors, continuous reactors, microreactors or static mixers can be used. The above-described method of the present invention is particularly suitable for conducting a coupling reaction in a static mixer or continuous stirred tank reactor containing a loop system. Advantageously, this reaction is processed in a batch mode.

  In a further aspect of the invention, embodiments of the invention include products produced according to this method of the invention. Specifically, the product produced is N- (n-propyl) -N- (3-fluoro-4-pyridinyl) -1H-3-methylindole-1-amine hydrochloride.

In yet another aspect of the present invention, there is also provided a compound of formula (IV), wherein the above substituents are as described herein, provided that R and R ₃ are hydrogen. R ₄ is not hydrogen or methyl.

As indicated above, some compounds within the scope of formula (IV) are known and are therefore excluded from the present invention. For example, Somei et al., Tet. Lett. 41, 3605-3608 (1974), which is incorporated herein by reference in its entirety, is that m is 0, R, R ₁ , R ₃ are H, R Compounds of formula (IV) are described where ₂ is methyl and R ₄ is methyl.

In a further aspect of this embodiment of the invention, preferred compounds of formula (IV) are those wherein R, R ₁ and R ₃ are hydrogen and R ₂ is methyl. Specific compounds within the scope of the present invention include, but are not limited to:
3-methyl-N- (propylidene) -1H-indole-1-amine,
N- (propylidene) -1H-indole-1-amine,
5-benzyloxy-N- (propylidene) -1H-indole-1-amine,
5-methoxy-N- (propylidene) -1H-indole-1-amine, and N- (propylidene) -1H-carbazol-1-amine.

  The invention is further illustrated by the following examples, which are provided for purposes of illustration and are not intended to limit the scope of the invention in any way.

Example (general description)
In the examples below, the following abbreviations are used:
HOSA hydroxylamine-O-sulfonic acid HPLC high performance liquid chromatography KotBu potassium tert-butoxide NMP N-methylpyrrolidinone NMR nuclear magnetic resonance General analytical technique used for characterization): using various analytical techniques Characterization of the compound produced according to the practice of the present invention, which included:

¹ H NMR spectra, ¹³ C NMR spectra and ¹⁹ F NMR spectra were recorded using a Varian XL300 spectrophotometer or Gemini 300 spectrophotometer operating at 300 MHz, 75 MHz and 282 MHz, respectively. ¹ H NMR spectral data are shown as δ in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, and the following abbreviations were used in the data summary: s = single line, d = Double line, t = triple line, q = quadruple line, m = multiple line, dd = double line double line, br = broad. The HPLC data was analyzed on a Perkin-Elmer Integral 4000 liquid chromatograph, typically a 3.9 × 150 mm, Waters Symmetry C ₁₈ column, 5μ, acetonitrile / 0.1N ammonium formate isocratic mobile phase, 1.0 mL / Collected using minute flow rate and UV detection. Mass spectra were obtained on a Finnigan TSQ 700 spectrometer. Elemental analysis was performed by Robertson Microlitt, Inc. Went by. Additional abbreviations used herein included: LC = liquid chromatograph; MS = mass analyzer; EI / MS = electrospray bombardment / mass analyzer; RT = retention time; M ⁺ = molecular ion .

Example 1
Hydroxylamine-O-sulfonic acid (HOSA) 33.8 kg (32.8 kg corrected for 97% purity) and indole 15.2 kg in 1H-indole-1-amine N-methylpyrrolidinone (NMP) An 8 kg (15.6 kg corrected for 99% purity) solution was prepared and cooled to 0-5 ° C. The second solution was charged with 67.0 kg (95% potassium tert-butoxide).
Adjusted to 6% kg) and NMP 122.6 kg. The amination vessel was charged with 47.0 kg of NMP and 2.2 kg of the initial charge of potassium tert-butoxide / NMP solution. The HOSA / indole / NMP solution and the rest in the amination vessel were then used for 185 minutes while maintaining the reaction temperature at 20-30 ° C. using a metering pumping system consisting of a double head plunger pump equipped with a Coriolis mass flow meter Of potassium tert-butoxide / NMP was charged simultaneously and in a balanced amount, and measured by an external standard HPLC assay, 15.9 kg of 1H-indole-1-amine (90. A solution containing 2% yield) was obtained.

Example 2
5-Benzyloxy-1H-indole-1-amine 5.3 kg hydroxylamine-O-sulfonic acid (HOSA) in 19.1 kg N-methylpyrrolidinone (NMP) (5.2 kg corrected for 97% purity) ) And was cooled to 0-5 ° C. A second solution was prepared from 10.6 kg of potassium tert-butoxide (10.0 kg corrected for 95% purity) and 19.3 kg of NMP. In the amination vessel, 5.0 kg of 5-benzyloxyindole (4.7 kg corrected for 94% purity), 15.5 kg of NMP and 0.4 kg of the initial charge of potassium tert-butoxide / NMP solution, Was loaded. The amination vessel is then charged with the HOSA / NMP solution and the remaining potassium tert-butoxide / NMP solution simultaneously and in a balanced amount over a 166 minute period while maintaining the reaction temperature at 14-29 ° C. A solution containing 4.3 kg (86.0% yield) of 5-benzyloxy-1H-indole-1-amine was obtained as determined by an external standard HPLC assay. After adding 105 L of water and cooling to 0-5 ° C., the mixture was filtered. The filtered solid was partitioned with 63 L of n-butyl acetate and 8.5 L of water and then filtered. The organic phase is concentrated under reduced pressure to give a solid containing 3.9 kg (77.4% yield) of 5-benzyloxy-1H-indole-1-amine as determined by external standard HPLC assay. It was.

Example 3
5-methoxy-1H-indole-1-amine 10.0 g hydroxylamine-O-sulfonic acid (HOSA) in 33.7 g N-methylpyrrolidinone (NMP) (9.7 g corrected for 97% purity) Was prepared and cooled to 0-5 ° C. The second solution was charged with 20.1 g of potassium tert-butoxide (9
Prepared from 19.1 g) and 34.4 g NMP, corrected for 5% purity. The amination vessel was charged with 5.9 g of 5-methoxyindole, 17.8 g of NMP and 0.7 g of the initial charge of potassium tert-butoxide / NMP solution. The HOSA / NMP solution and the remaining potassium tert-butoxide / NMP solution were then charged simultaneously and in proportion to the amination vessel over 86 minutes while maintaining the reaction temperature at 15-22 ° C. A solution containing 5.6 g (87% yield) of 5-methoxy-1H-indole-1-amine was obtained as determined by an internal standard HPLC assay.

Example 4
Prepare a solution of 10.0 g of hydroxylamine-O-sulfonic acid (HOSA) (9.7 g corrected for 97% purity) in 35.9 g of 1H-carbazol-1-amine N-methylpyrrolidinone (NMP) And cooled to 0-5 ° C. The second solution was charged with 20.3 g of potassium tert-butoxide (9
Prepared from 19.3 g) and 35.3 g NMP, corrected for 5% purity. The amination vessel was charged with an initial charge of 7.0 g carbazole (6.7 g corrected for 99% purity), 21.7 g NMP and 1.3 g potassium tert-butoxide / NMP solution.
The HOSA / NMP solution and the remaining potassium tert-butoxide / NMP solution were then charged simultaneously and in proportion to the amination vessel over 86 minutes while maintaining the reaction temperature at 22-30 ° C. A solution containing 85% yield of 1H-carbazol-1-amine was obtained as determined by HPLC.

Example 5
1H-3-methyl-indole-1-amine 35.6 kg of potassium tert-butoxide and 63.1 kg of N-methylpyrrolidinone (NMP) were charged to a 30 gallon Hastelloy reactor under nitrogen and then 20-2
A 36.1% (wt / wt) solution of KOtBu / NMP (sufficient for two amination batches) was prepared by stirring at 5 ° C. for 30 minutes. NMP 75.4 kg and HOSA total 17.7 kg (divided into 3 parts over 45 minutes) were charged into a 30 gallon Hastelloy reactor under nitrogen and stirred at 30-35 ° C. for 40 minutes (until dissolution occurred) Then, a 19.0% (wt / wt) solution of hydroxylamine-O-sulfonic acid (HOSA) in NMP (sufficient for two amination batches) was prepared by cooling to 10 ° C.
Under nitrogen, 4.5 kg (34.3 mol) of 3-methylindole, 10.0 L of NMP and 0.4 kg (0.1 equivalent) of potassium tert-butoxide were charged into a 30 gallon glass-lined reactor. A container was prepared. Using a proportional pumping system consisting of a double head plunger pump and a pair of mass flow meters, the HOSA solution at 0.47 kg / min and the KOtBu solution at 0.49 kg / min into the amination reactor (this amination vessel (Through a sparging tube below the liquid level) at the same time. The temperature of the slightly exothermic amination process was controlled at 25-35 ° C by adjusting with jacket cooling. Feeding was stopped after 90 minutes at which time a total of 43.9 kg (4.1 equivalents) of KOtBu solution and 42.0 kg (2.1 equivalents) of HOSA solution were charged and N-amino-3-methyl-indole 97% conversion to was achieved (by HPLC assay). The post-treatment was performed in two parts. Half of the batch was transferred to a quench vessel (30 gallon reactor) containing 60 L of cold water and 12 L of toluene. After stirring for 10 minutes at 20-25 ° C., the phases were separated. The aqueous phase was extracted 3 times with 12 L of toluene. The other half of the batch was similarly post-treated. The organic phases from each part of the workup were combined and concentrated (60 ° C., <50 mbar, 50 L rotary evaporator) to give 5.2 kg of N-amino-3-methylindole as a pasty solid (this is NMR (Corresponding to 4.5 kg of product with correction of solvent 3.4 wt% and NMP 6.9 wt%), yield 89.7%, purity 95.9% by HPLC assay.
Similarly, a second amination was performed following the same procedure as described above using the remainder of the HOSA and KOtBu solution, and 4.6 kg of N-amino-3-methylindole (
Corrected), yield 91.1%.

Example 6
1H-indole-1-amine Step 1-Preparation of HOSA / indole solution: A 50 gallon glass lined steel reactor was charged with 120.2 kg (116.3 L) of NMP under a nitrogen purge and slight evacuation, while The reactor temperature was maintained at 19-23 ° C. While stirring (about 130 rpm), HOSA33.
Divide 8 kg (32.8 kg corrected for 97% purity) into 3 parts (about 15.8 kg)
, 9.0 kg and 9.0 kg) were fed through a manhole about every 15-30 minutes. The initial calorific value was expected to be a 10-15 ° C temperature rise. Cold water was circulated through the jacket or gentle jacket heating was used to maintain the pot temperature at 20-35 ° C (preferably 30-35 ° C to promote dissolution). Dissolution was expected 1-2 hours after stirring. The reactor contents were cooled to a temperature of about 20 ° C. (10-25 ° C.) and 15.8 kg of indole (15.6 kg corrected for 99% purity) was fed through the manhole. After dissolution (several minutes), the reactor contents are cooled to a temperature of about 0-5 ° C. (−5-15 ° C.), stirring is reduced to about 50 rpm, and then the temperature is about 0-5 for the remainder of the process. Maintained at ℃ (-5 to 15 ℃).

Step 2-Preparation of potassium tert-butoxide solution: NMP 122.6 under nitrogen purge and slight evacuation to a 50 gallon glass lined steel reactor with empty condenser piping.
kg (118.7) was charged while the reactor temperature was maintained at about 17-19 ° C (15-22 ° C). Potassium tert-butoxide (KOtBu) 67.0 kg (63.7 kg corrected for 95% purity) was passed through the manhole at about 150 rpm (100-200 r).
pm) with stirring. A slight exotherm up to 20-25 ° C was observed. Cooled if necessary to maintain the temperature below 25 ° C. After dissolution was achieved (within 15-60 minutes), the remainder of the process was stirred at a temperature of about 50 rpm and about 17-25 ° C.

Step 3—Amination: A 150 gallon glass lined steel reactor was charged with 47.0 kg (45.5 L) of NMP under nitrogen purge and slight evacuation and brought to 10-22 ° C. with stirring at about 180 rpm. Cooled down. An initial amount of about 0.05 equivalents of the KOtBu solution from Step 2 was charged (6.7 moles, total solution 2.2 kg). The two solutions prepared above in steps 1 and 2 were then added to the following rate (HOSA / indole solution from step 1 at a rate of 0.8 L / min = 0.9 kg / min for a total time of 187.4 min. And KOtBu solution from step 2 1.
0 L / min = 1.0 kg / min for a total time of 187.4 minutes) with good stirring (> 180 rpm) and using cold water cooling, the reaction temperature is about 15-30 ° C., preferably 24-30 Maintained at 0 ° C. and pumped simultaneously through a sparging tube (3/8 inch outer diameter 304 SS tubular material) inserted into the nozzle on the opposite side of the reactor head (approximately 180 degrees away). Withdraw the sample of the reaction mixture for HPLC assay as described in further detail below, with reaction progress at 0.5 HOSA equivalence intervals (every 43 minutes 35 seconds between simultaneous reagent charges). Monitored by All reagents (133.5 molar scale) were charged and the supply of simultaneous and balanced amounts was continued until the amination was judged complete as indicated by the HPLC assay. Both reactors from step 1 and step 2 were each rinsed with 5 L of NMP, and the rinse was pumped into the 150 gallon reactor of this step. The batch from this step was then used as such in the next step in the preparation of N-propylidene-1H-indole-1-amine.
The reaction mixture was monitored by HPLC assay using the following conditions.
Column: Phenomenex, IB-SIL 5 phenyl, 150 × 4.6 mm, 5 micron Mobile phase: 65:35 0.1 N ammonium formate / acetonitrile Flow rate: 1.5 mL / min Detection: UV at 275 nm
Sample preparation: Approximately 15 μL of reaction mixture was diluted with 2 mL of mobile phase 50:50 mixture.
Injection: 10 μL

Example 7
N-propylidene-1H-indole-1-amine In a 150 gallon steel reactor prepared according to the procedure shown in Example 6, 10-25 ° C. with nitrogen purge, slight evacuation, stirring at about 150 rpm, preferably 10-18
To the 1H-indole-1-amine solution prepared at 0 ° C. and slowly jacket cooling, about 21.6 kg of acetic acid to pH 3.9-4.0 (0.1 mL of reaction mixture in 5 mL of water), about 1 kg / Charged at a speed of minutes. More HOAc was supplied in increments if necessary to achieve this pH level. The pump was rinsed with about 2L NMP. Essentially once (about 1 minute addition time), 10.8 L of water was fed (a slight temperature increase of about 3-6 ° C. was expected). Propionaldehyde 14.4 kg (13.9 kg corrected for 97% purity) at about 0.8 kg / min (0.5-1.0 kg / min) at 10-24 ° C., preferably 10-20 It was charged while maintaining at ℃. A mild fever was expected. A temperature increase of about 5 ° C. was expected, depending on the rate of addition and cooling. The pump was rinsed with about 3L NMP. Stirring at 10-24 ° C., preferably 17-20 ° C., until the reaction was judged complete as indicated by HPLC assay, this condition is further detailed below (99% over 2-3 hours) Conversion). The progress of the reaction was monitored by removing a sample of the reaction mixture for the HPLC assay. When the reaction was judged complete, a vacuum distillation was prepared directly from the reactor to a suitable receiver. Initially, a pre-fraction (about 45-50 L) of volatile materials including tert-butanol and water was expected at 50-70 ° C. and about 30-40 mm pressure. As the distillation rate slowed, the pot temperature gradually increased to 95-100 ° C., the pressure decreased to 5-25 mm, and NMP collection began. Collect a total of about 320 kg of distillate (giving a pot weight of 9.5 parts w / w for the initial indole charge), then release the vacuum with nitrogen and bring it to 10-25 ° C. Cooled down. If necessary, or for scheduling convenience, the distillation can be performed at any time by releasing the vacuum with nitrogen, cooling to below 30 ° C., storing under nitrogen, and then restarting as necessary. Could be interrupted. The reaction was processed by feeding 234 L of water through the reactor feed nozzle with 133 L of heptane, followed by cold water cooling to maintain the exothermic temperature below 30 ° C. (maximum process volume of about 450 L was achieved). Stir for more than 10 minutes and then separate the phases. The bottom aqueous phase was extracted with 54 L heptane. The organic extracts were combined and washed with aqueous potassium bicarbonate (prepared from 0.6 kg potassium bicarbonate dissolved in 58 L water (58-95 L)) followed by 58 L water. The organic phase was concentrated to give crude N-propylidene-IH-indole-1-amine as an oil. Short path distillation, ie an evaporator at about 120 ° C. and a first flow path at about 200-800 mbar pressure to remove volatiles, then an evaporator at 110 ° C. and 0.2-0.4 mbar pressure And purified product was collected by the second route.
The reaction mixture was monitored by HPLC assay using the following conditions.
Column: Phenomenex, IB-SIL 5 phenyl, 150 × 4.6 mm,
5 micron Mobile phase: 65:35 0.1 N ammonium formate / acetonitrile Flow rate: 1.5 mL / min Detection: UV at 275 nm
Sample preparation: 2 drops of reaction mixture per mL of acetonitrile was added and 10 μL was injected.

Example 8
Potassium tert-butoxide in 160 mL of N- (propylidene) -1H-indole-1-amine N-methylpyrrolidone (NMP) 86.
A 6 g (771 mmol) solution was prepared. A solution of 36.4 g (322 mmol) of hydroxylamine-O-sulfonic acid (HOSA) in 175 mL of NMP was also prepared. After obtaining a clear solution, the HOSA solution was cooled to 10 ° C.
In addition, prepare a 11.9 g (102 mmol) solution of indole in 20 mL of NMP,
An initial amount of 0.08 to 0.12 equivalents of KOtBu solution was added to the indole solution. The HOSA solution and KOtBu solution were then added to the reaction mixture at 20 ° C. simultaneously and in balanced amounts via a double syringe pump over 60 minutes. After completion of this addition, 9 mL (500 mmol) of water, 12 mL (300 mmol) of glacial acetic acid and 15 mL (173 mmol) of propionaldehyde were added to the resulting dark brown suspension. The mixture was stirred at 20 ° C. until the reaction was complete. The reaction mixture was then worked up by adding 500 mL of water and 200 mL of n-heptane. The phases were separated. The aqueous phase was again extracted once with 300 mL n-heptane and again extracted twice with 200 mL toluene. The combined organic phases were washed twice with 100 mL water. The resulting brown heptane solution was evaporated to dryness. Thus, 14 g (80%) of N- (propylidene) -1H-indole-1-amine was obtained as a brown liquid.
bp 130-135 ° C (1.3-1.4mbar)
¹ H-NMR (DMSO-d ₆ , 300 MHz, TMS) [δ, ppm]: 1.2 (t,
3H, CH ₃ ), 2.5 (m, 2H, CH ₂ ), 6.6 (d, 1H, aromatic), 7.1 (t, 1H, aromatic), 7.2 (t, 1H, Aromatic), 7.6 (dd, 2H, aromatic), 8.0 (d, 1H, aromatic), 8.2 (t, 1H, NCH)
MS (EI +, 70 eV): 172 [M ⁺ ], 116 [M ⁺ -NC ₃ H ₆ ]

Example 9
N-propyl-1H-indole-1-amine A solution of 12.3 g (69.7 mmol) of N- (propylidene) -1H-indole-1-amine in 45 mL of NMP was prepared and 1.6 g of sodium borohydride (41 0.8 mol) was added. A solution of 2.5 g (41.8 mmol) of glacial acetic acid in 15 mL of NMP was then prepared. This acetic acid solution was added to the above reaction mixture at 30 ° C. for about 30 minutes. Hydrogen evolution occurred immediately. The reaction mixture was stirred at 35 ° C. until the reaction was complete. Upon completion of the reaction, the reaction mixture was worked up by slowly adding 50 mL of water at 35 ° C. Care was taken during the addition of water to minimize foaming that occurred and sufficient headspace was provided for foaming. Free headspace was maintained as much as three times the liquid volume of the reactor to control foaming. The reaction mixture was extracted with 50 mL n-heptane, the phases were separated, and the aqueous phase was extracted again with 25 mL n-heptane. The combined organic phases were evaporated to dryness. In this manner, 10.9 g (90%) of N-propyl-1H-indole-1-amine was obtained as a brown liquid.
bp 115-125 ° C. (1.1 mbar)
¹ H-NMR (DMSO-d ₆ , 300 MHz, TMS) [δ, ppm]: 0.9 (t, 3H, CH ₃ ), 1.35 (m, 2H, CH ₂ ), 3.0 (m, 2H, NCH ₂ ), 6.35 (d, 1H, aromatic), 6.5 (t, 1H, NH), 7.0 (t, 1H, aromatic), 7.15 (t, 1H, aromatic Group), 7.4 (m, 1H, aromatic), 7.5 (dd, 2H, aromatic)
MS (EI +, 70 eV): 174 [M ⁺ + H], 131 [M ⁺ + H—NHC ₃ H ₇ ]

Example 10
(3-Fluoropyridin-4-yl)-(indol-1-yl) -propylamine hydrochloride A solution of 18.0 g potassium tert-butoxide in 53 mL NMP is prepared and this suspension is obtained until a clear solution is obtained. The solution was stirred at 20 ° C. The solution was cooled to -20 ° C. While maintaining the internal reaction temperature at about −15 ° C., 9.3 g (53.4 mmol) of N-propyl-1H-indole-1-amine, 7.4 g of 4-chloro-3-fluoropyridine were added to this cooled solution. A mixture of (53.4 mmol) and 53 mL of NMP was added. After completion of the addition, the reaction mixture was stirred for about 30 minutes at -20 ° C. The reaction mixture was then added to 100 mL water and 13 mL HCl (37%). Then 50 mL of n-heptane (2 ×) was added and the phases were separated. To the aqueous phase was added 10 mL NaOH (32%) and the aqueous phase was extracted twice with 50 mL n-butyl acetate and the combined n-butyl acetate phases were washed with 50 mL water. To the resulting n-butyl acetate phase, 4.5 mL of HCl (37%) was added. The mixture was distilled using a Dean Stark trap to completely remove the water. A solid precipitated during the distillation. The suspension was cooled to 5 ° C. and filtered. After drying at 60-70 ° C., 10.8 g (75%) of (3-fluoropyridin-4-yl)-(indol-1-yl) -propylamine hydrochloride remained as a slightly yellow solid.
¹ H-NMR (DMSO d ₆ , 300 MHz, TMS) [δ, ppm]: 0.9 (t,
3H, CH ₃ ), 1.65 (m, 2H, CH ₂ ), 4.0 (dm, 2H, NCH ₂ ),
6.35 (t, 1H, aromatic), 6.7 (d, 1H, aromatic), 7.2 (m, 2H, aromatic), 7.4 (d, 1H, aromatic), 7. 65 (d, 1H, aromatic), 7.7 (d
, 1H, aromatic), 8.25 (d, 1H, aromatic), 8.9 (d, 1H, aromatic)
MS (CI +): 270 [ M + + H, free base]

Example 11
3-methyl-N- (propylidene) -1H-indole-1-amine A solution of 44.7 kg (398 mol) of potassium tert-butoxide in 80 kg of N-methylpyrrolidone (NMP) was prepared. In addition, a 21.5 kg (190 mol) solution of hydroxylamine-O-sulfonic acid (HOSA) in 98 kg of NMP was prepared and the HOSA solution was cooled to 10 ° C. after a clear liquid was obtained.
Prepare a 10 kg (76.2 mol) solution of 3-methylindole in 50 kg of NMP,
An initial amount of 0.08 to 0.12 equivalents of KOtBu solution was then added to the 3-methylindole solution. The HOSA and KOtBu solutions were added to the reaction mixture at 20 ° C. via a mass flow meter in simultaneous and balanced amounts over 120 minutes. After the addition was complete, 6.9 L (381 mol) of water, 13.7 kg (228.6 mol) of acetic acid (100%) and 7.5 kg (129.2 mol) of propionaldehyde were added to the resulting dark brown suspension. did. The mixture was stirred at 20 ° C. for about 1 hour until the reaction was complete. The reaction mixture was then treated by the addition of 248 L water and 42 kg n-heptane. Undesirable salts precipitated from the reaction mixture. The resulting suspension was filtered and the phases were separated. The aqueous phase was again extracted 3 times with 42 kg of n-heptane. The combined organic phases were washed twice with 63 L of water. The resulting brown heptane solution was evaporated to dryness. Thus, 11.6 to 12.5 kg (yield 81 to 90%) of 3-methyl-N- (propylidene) -lH-indole-l-amine was obtained as a brown liquid.
bp 121-123 ° C. (1 mbar)
¹ H-NMR (300 MHz, DMSO-d ₆ , TMS) [δ, ppm]: 1.15 (t
_{, 3H, CH 3), 2.3} (s, 3H, CH 3), 2.45 (m, 2H, CH 2), 7.05 (t, 1H, aromatic), 7.2 (t, 1H , Aromatic), 7.5 (2d, 2H, aromatic), 7.8 (s, 1H, aromatic), 8.05 (t, 1H, NCH)
MS (CI +): 187 [M ⁺ + H], 130 [M ⁺ -NC ₃ H ₆ ]

Example 12
3-methyl-N-propyl-1H-indole-1-amine In an 800 L vessel, 3.0 kg (74.4 mol) sodium borohydride and 108-methyl 3-N- (propylidene) -1H-indole in 108 kg NMP 1-amine 26.
An 8 kg (124 mol, 86% purity) solution was prepared. A 4.5 kg (74.4 mol) glacial acetic acid solution in 27 kg NMP was prepared. This acetic acid solution is added over 30 minutes for about 30 minutes.
Added to the sodium borohydride solution at 0 ° C. Soon hydrogen was generated. The reaction mixture was stirred at 30 ° C. until the reaction was complete (about 1 hour). 6.3 kg of ethanol was added to the reaction mixture and foaming occurred immediately. The reaction mixture was then treated by carefully adding an additional 80 L of water. Care was taken during the addition of water, so that foaming was controlled, and in particular the slow addition of water first was recommended to prevent uncontrolled foaming. Care was taken to ensure that no foaming or minimal foaming occurred during the first 1-2 liters of water. The reaction mixture was left overnight. The aqueous phase was extracted 3 times with 45 kg of n-heptane and the combined organic phases were washed with 66 L of water. The combined organic phases were evaporated to dryness. Thus, 22.4 kg (yield 90%, 94% purity) of 3-methyl-N-propyl-1H-indole-1-amine was obtained as a brown liquid.
¹ H-NMR (300 MHz, DMSO d ₆ , TMS) [δ, ppm]: 0.9 (t,
3H, CH ₃ ), 1.4 (m, 2H, CH ₂ ), 2.2 (s, 3H, CH ₃ ), 2.95 (m, 2H, NCH ₂ ), 6.3 (t, 1H, NH), 7.0 (t, 1H, aromatic),
7.1 (t, 1H, aromatic), 7.15 (s, 1H, aromatic), 7.4 (d, 1H, aromatic)
Aromatic), 7.45 (d, 1H, aromatic)
MS (CI +): 189 [M ⁺ + H], 130 [M ⁺ -NC ₃ H ₇ ]

Example 13
3-Methyl-N-propyl-1H-indole-1-amine A solution of sodium borohydride (4.54 kg, 120 mol) in 38 kg NMP was prepared. To this solution was added a solution of 3-methyl-N- (propylidene) -1H-indole-1-amine (38.6 kg, 190 mol) in 78 kg of n-heptane. A solution of 6.8 kg (120 mol) of glacial acetic acid in 32 kg of n-heptane was prepared. This acetic acid solution was added to the sodium borohydride solution at 30 ° C. over about 30 minutes using a pump. Immediately hydrogen evolution occurred. The pump was rinsed with 3 kg of n-heptane and this rinse was added to the reaction mixture. The reaction mixture was stirred at 30 ° C. until the reaction was complete (about 1 hour). The reaction mixture was then worked up by adding 76 L of water. During the addition of water, it was observed that no foaming or minimal foaming occurred. The mixture was stirred overnight and the phases were separated. 2.82 kg (30%) of HCl and 4.75 kg of water were added to the n-heptane phase, the pH was checked, and if the pH exceeded 1, more HCl was added. The mixture was heated to an internal temperature of 75 ° C. for about 2 hours. The mixture was cooled to 25 ° C. to control hydrogen evolution. If no more residual hydrogen was generated, the pH level was adjusted to 7, an additional 30 kg of water was added, the phases were separated, and the n-heptane phase was washed twice with 37 kg of water. The n-heptane phase was evaporated to dryness. There was thus obtained 37.5 kg (98%) of 3-methyl-N-propyl-1H-indole-1-amine as a brown liquid.

Example 14
(3-Fluoropyridin-4-yl)-(3-methylindol-1-yl) -propylamine hydrochloride Prepare a 58.8 kg solution of potassium tert-butoxide in 135.8 kg NMP until a clear solution is obtained The suspension was stirred at 20 ° C. and was called Solution A.
3-Methyl-N-propyl-1H-indole-1-amine 3 in 68.5 kg NMP
6.1 kg (175.6 mol) and 4-chloro-3-fluoropyridine 24.3 kg (1
84.4 mol) solution was prepared and called Solution B.
Both solution A and solution B as prepared above are added simultaneously to the reactor while maintaining the internal temperature at −20 ° C. (solution A is about 24 kg / hour, and solution B is about 17.2 kg / hour. Time)
The reactor was prefilled with 15 kg NMP and 2 kg solution A. The amount of liquid in the reaction vessel was kept steady at the same level during the complete addition of Solution A and Solution B by discharging the mixed solution into another vessel. The reaction solution thus collected in a separate container was quenched with 19 kg of water. After all amounts of Solution A and Solution B were added, the reactor was washed with 20 kg NMP. For further work-up, 275 kg of water was added and the basic aqueous phase was extracted 4 times with 57 kg of n-heptane. The combined n-heptane phases were extracted twice with 175 kg of water and 13.2 kg of HCl (30%), the phases were separated, and 30.9 kg of NaOH solution (33%) were added to the aqueous phase. The aqueous phase was extracted twice with 155 kg of n-butyl acetate and the combined n-butyl acetate phases were washed with 176 kg of water. A sample of n-butyl acetate extract was removed and analyzed for free base. Based on this analysis, the n-butyl acetate phase was diluted to contain about 10% (w / w) free base. Water was removed under vacuum and 18.5 kg of HCl (30%) was added to the resulting n-butyl acetate phase. The mixture was distilled using a Dean Stark trap to completely remove the water. A solid precipitated during the distillation. The suspension was cooled to 5 ° C. and filtered. The filter cake was washed twice with 76 kg of n-butyl acetate. After drying at 60-70 ° C., 43.8 kg (77.3%) of (3-fluoropyridin-4-yl)-(3-methylindol-1-yl) -propylamine hydrochloride as a slightly yellow solid Remained.
mp 219 ° C. (DSC, heating rate 5 ° C./min, HCl loss and decomposition)
¹ H-NMR (300 MHz, DMSO-d ₆ , TMS) [δ, ppm]: 0.9 (t,
3H, CH ₃ ), 1.7 (m, 2H, CH ₂ ), 2.5 (m, 3H, CH ₃ ), 4.0 (dm, 2H, CH ₂ ), 6.3 (m, 1H, Aromatic), 7.2 (m, 2H, aromatic),
7.3 (m, 1H, aromatic), 7.4 (d, 1H, aromatic), 7.7 (dd, 1H, aromatic), 8.2 (d, 1H, aromatic), 8. 9 (d, 1H, aromatic)
MS (EI +, 70 eV): 283 [M ⁺ , free base], 240 [M ⁺ -C ₃ H ₇ ], 130 [3-methylindole fragment], 96 [fluoropyridine fragment]

Example 15
4-Chloro-3-fluoropyridine A 30-gallon Hastelloy reactor was charged with 2.5 kg (25.8 mol) of 3-fluoropyridine and 3.4 kg (29.6 mol) of tetramethylethylenediamine (TMEDA) under nitrogen. 2 liters) and 20 L methyl tert-butyl ether (MTBE).
The solution was cooled to -50 ° C. A total of 15.5 L (12.6 L, 29.6 mol, 1.15 eq) of a 1.9 M lithium diisopropylamide (LDA) solution (heptane / THF / ethylbenzene) was maintained at a temperature between −40 and −48 ° C. Added over 24 minutes. The light brown suspension was stirred at -44 to -48 ° C for 50 minutes. A solution of 7 kg (29.6 mol, 1.15 eq) hexachloroethane in 20 L MTBE was added over 48 minutes while maintaining the temperature between -40 and -46 ° C. After stirring at −40 ° C. for 20 minutes, the reaction was warmed to 0 ° C. and then quenched in a reactor containing 54 L of cold water. After stirring for 20 minutes at 20-25 ° C., the mixture was filtered through celite to break up a slight emulsion. The layers were separated. The aqueous layer was extracted with 5 L MTBE. The organic layers were combined and then extracted with a portion of 2N HCl (1 × 21 L, 3 × 13 L). The acidic aqueous phases were combined and partitioned with MTBE 16 L, then basified to pH 6.19 by adding 6.5 kg of 50% NaOH while maintaining the temperature at 15-20 ° C. The layers were separated. The aqueous phase was extracted with 10 L MTBE. The combined organic phases are dried over 3.0 kg of sodium sulfate, then filtered and concentrated (56 ° C., 575 mbar for most of the concentration, 400 mbar for final concentration) to give 4-chloro- 3.7 kg of 3-fluoropyridine were obtained (2.4 kg corrected for 31.2% of solvent by NMR and 95.5% purity by HPLC, yield of 70.2%).

Example 16
(3-Fluoropyridin-4-yl)-(3-methylindol-1-yl) -propylamine hydrochloride A solution of 510 g (4.5 mol) of potassium tert-butoxide in 1190 g of NMP is prepared, giving a clear solution. The suspension was stirred at 20 ° C. until (solution A).
3-methyl-N-propyl-1H-indole-1-amine 154.1 g (769 mm)
ol, 94% purity), 112.7 g (846 mmol) of 4-chloro-3-fluoropyridine.
, 99% purity) and 622 g of NMP were prepared (Solution B).
A loop system connected by a loop pump to a continuous stirred tank reactor (CSTR) and a static mixer was filled with 950 g of solution A. The loop system was cooled to -15 ° C. Supply of solution A to the CSTR and supply of solution B from the static mixer were started and both solutions were added under temperature control (−15 ° C.) for 53 minutes. During the addition, the amount in the CSTR was kept constant (approximately 360 mL). The reaction mixture was quenched with 247 g of water. At the end of the feed, the loop system was drained and the system was rinsed with 951 g of water. An additional 1224 g of water was added to the rinse and the quenched reaction solution. The aqueous phase was extracted 4 times with 380 g of n-heptane. The resulting n-heptane phase was extracted twice with a solution of 771 g water and 45.4 g HCl (37%). To the resulting aqueous phase, 131 g of NaO (33%) was added and extracted twice with 680 g of n-butyl acetate. The obtained n-butyl acetate phase was washed once with 775 g of water. 79.6 g of HCl (37%) was added and the resulting mixture was distilled under vacuum using a Dean-Stark trap until no more water was removed. The reaction mixture was cooled to 5 ° C. so that the product began to crystallize and the product was filtered. Dry in a shelf dryer under vacuum. There was thus obtained 164.4 g (yield 71%) of 3-fluoropyridin-4-yl- (3-methylindol-1yl) -propylamine hydrochloride.

Example 17
A solution of 26.8 kg (239 mol) of potassium tert-butoxide (KOtBu) in 50 kg of N- (propylidene) -1H-indole-1-amine N-methylpyrrolidone (NMP) was prepared. In addition, a 13.8 kg (120 mol) solution of hydroxylamine-O-sulfonic acid (HOSA) in 71 kg NMP was prepared and the HOSA solution was cooled to 10 ° C. until a clear liquid was obtained.
A solution of 6.4 kg (54.6 mol) indole was prepared in 25 kg NMP. To this solution, the HOSA solution and KOtBu solution prepared above were added simultaneously and in balanced amounts over 180 minutes via a mass flow meter, and the reaction mixture was maintained at 15 ° C. After completion of the addition, 4.3 L (239 mol) of water, 9.7 kg (161.5 mol) of acetic acid (100%) and 5.3 kg (91.3 mol) of propionaldehyde were added to the resulting dark brown suspension. . The mixture was stirred at 20 ° C. for about 1 hour until the reaction was complete. The reaction mixture was then treated by the addition of 180 L water and 21 kg n-heptane. Unwanted salts precipitated from the reaction mixture. The resulting suspension was filtered and the phases were separated. The aqueous phase was again extracted four times with 21 kg of n-heptane. The combined organic phases were washed twice with 45 L of water. The resulting brown heptane solution was evaporated to a 15-25% solution. This gave 6.3-7.0 kg of N- (propylidene) -1H-indole-1-amine as a brown liquid (yield 67-74% corrected for 19.7-24.1% analysis). It was.
¹ H-NMR (400 MHz, DMSO-d ₆ , TMS) [δ, ppm]: 1.19 (t
, 3H, CH ₃ ), 2.48 (m, 2H, CH ₂ ), 6.60 (d, 1H, aromatic), 7.08 (t, 1H, aromatic), 7.22 (t, 1H , Aromatic), 7.57 (d, 1H
, Aromatic), 7.61 (d, 1H, aromatic), 8.03 (d, 1H, aromatic), 8.
19 (t, 1H, NCH)
MS (ES +): 173 [M ⁺ + H], 117 [M ⁺ -NC ₃ H ₆ ]

Example 18
N-propyl-1H-indole-1-amine A solution of 0.83 kg (21.9 mol) sodium borohydride in 16.6 kg NMP was prepared. 31.9 kg of N- (propylidene) -1H-indole-1-amine was added as a 19.7% solution in n-heptane (36.5 mol) and an additional 7.7 kg of n-heptane was added. A solution of 1.32 kg (21.9 mol) of glacial acetic acid in 2.8 kg of n-heptane was prepared. This acetic acid solution was added to the sodium borohydride solution at 30 ° C. over about 30 minutes using a pump. Immediately hydrogen evolution occurred. The pump was rinsed with 2 kg of n-heptane. The reaction mixture was stirred at 30 ° C. until the reaction was complete (about 1 hour). The reaction mixture was then treated by adding 20 L of water. During the addition of water, it was observed that no foaming or minimal foaming occurred. The mixture was stirred overnight and the phases were separated. 0.9 kg of HCl (30%) and 3.4 kg of water were added to the n-heptane phase to check if the pH was less than 1. An additional amount of HCl was added if necessary to adjust the pH to about 1. The mixture was heated to an internal temperature of 75 ° C. for about 2 hours. The mixture was cooled to 25 ° C. to control the residual hydrogen generated. If no more residual hydrogen was generated, an additional 20.3 kg of water was added and the pH was adjusted to a level above 7 with NaOH (33%). The phases were separated and the n-heptane phase was washed with 20.3 kg of water. The n-heptane phase was evaporated to dryness. In this way, 5.84 kg (82.6%) of N-propyl-1H-indole-1-amine was obtained as a brown liquid.
¹ H-NMR (400 MHz, DMSO-d ₆ , TMS) [δ, ppm]: 0.91 (t
, 3H, CH ₃ ), 1.35 (m, 2H, CH ₂ ), 3.00 (m, 2H, CH ₂ ),
6.33 (d, 1H, aromatic), 6.43 (t, 1H, NH), 7.12 (t, 1H,
Aromatic), 6.98 (t, 1H, aromatic), 7.35 (d, H, aromatic), 7.46 (d, 1H, aromatic), 7.50 (d, 1H, aromatic) )
MS (ES +): 175 [ M + + H]

Example 19
Indol-1-yl-propyl-pyridin-4-yl-amine hydrochloride 12.4 kg (110.7 mol) potassium tert-butoxide in 23.6 kg NMP
) A solution was prepared and the suspension was stirred at 20 ° C. until a clear solution was obtained (solution A).
A second solution of 5.84 kg (27.7 mol, analysis 82.6%) of N-propyl-1H-indole-1-amine and 4.36 kg (29.1 mol) of 4-chloropyridine hydrochloride was dissolved in 15 kg of NMP. Prepared (Solution B).
Solution A was added to Solution B while maintaining the temperature at 20 ° C. Stir for 1 hour and check reaction completion. The reaction mixture was quenched in 135 kg of water. The pH value of this solution was adjusted to about 2 using HCl (30%) and extracted twice with 20 kg of n-heptane. The organic layer was discarded. The pH value of the aqueous layer was adjusted to 12 with NaOH (33%) and extracted twice with 16 kg of n-butyl acetate. The aqueous layer was discarded. The organic layer was washed with 23 kg of water. 10.8 kg of methanolic HCl (29.9 mol, analysis 10.1%) was added to the organic layer at 20 ° C. After crystallization, the mixture was cooled to 5 ° C., the product was filtered and washed with n-butyl acetate. Dry in a shelf dryer at 80 ° C. under vacuum. There was thus obtained 5.8 kg (73% yield) of indol-1-yl-propyl-pyridin-4-yl-amine hydrochloride as a white to beige solid.
¹ H-NMR (400 MHz, DMSO-d ₆ , TMS) [δ, ppm]: 0.94 (t
, 3H, CH ₃ ), 1.62 (m, 2H, CH ₂ ), 4.05 (dm, 2H, CH ₂ ),
6.74 (d, 1H, aromatic), 7.19 (m, 1H, aromatic), 7.28 (m, 1H, aromatic), 7.30 (d, 1H, aromatic), 5. 8 to 7.6 (s v br, 2H
, Aromatic), 7.63 (d, 1H, aromatic), 7.70 (d, 1H, aromatic), 8.
43 (dbr, 2H, aromatic), 15.2 (sbr, 1H, NH ⁺ )
MS (ES +): 252 [ M + + H, free base]

  The following examples illustrate N-aminated products obtained by following the procedure set forth in EP 0 249 452.

Comparative Example 1
1H-indole-1-amine A solution of 3.3 g (3.2 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 7.7 g of water is prepared, and 0-5 Cooled to ° C. An amination vessel was charged with 10.0 g of indole and 50.0 g of water. The HOSA / water solution and 7.3 mL of 30% NaOH solution were then simultaneously metered into the amination vessel over 120 minutes while maintaining the reaction temperature at 20-25 ° C. HPLC analysis indicated that 1H-indole-1-amine was not formed.

  The present invention is illustrated by some of the above examples, but should not be construed as limited thereby. Rather, the present invention encompasses the general scope as disclosed hereinabove. Various changes and embodiments may be made without departing from the spirit and scope of the invention.

Claims (55)

(A) preparing a hydroxylamine-O-sulfonic acid solution in a suitable organic solvent;
(B) preparing a suitable base solution in a suitable organic solvent;
(C) Formula I in a suitable organic solvent:

A solution of the compound of
(D) contacting the solution from step (a) and the solution from step (b) with the solution from step (c) contained in a suitable reaction vessel simultaneously and in a balanced amount at a suitable reaction temperature; Obtaining a compound of formula (II) with high purity and high yield,
Comprising the steps of formula II:

A method for producing the compound.
In the above formula,
R is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or fluoroalkyl of formula C _n H _x F _y or fluoroalkoxy of formula OC _n H _x F _y , where n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1;
R ₁ and R ₂ are the same or different and each is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or a fluoroalkyl of formula C _n H _x F _y or formula OC _n H _x F _y independently selected from fluoroalkoxy, where n is an integer from 1 to 4;
x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1, or R ₁ and R ₂ are taken together with the carbon atom attached to them. C ₅ -C ₈ cyclic ring to form Te, and m is 1 or 2.   The method according to claim 1, wherein the solvent in step (a) and step (b) is an aprotic solvent.   The process according to claim 2, wherein the aprotic solvent is N-methylpyrrolidinone.   The process according to claim 2, wherein the solvent is N, N-dimethylformamide.   The process according to claim 2, wherein the solvent is N, N-dimethylacetamide.   The method according to claim 1, wherein the base in step (b) is an organic base. The method of claim 6 base has at least substantially the same pK _a value and pK _a values of the indole.   The method according to claim 6, wherein the organic base is an alkali metal alkoxide.   Alkali metal alkoxide is lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium 9. A process according to claim 8 selected from the group consisting of isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide and cesium tert-butoxide.   The process according to claim 8, wherein the alkali metal alkoxide is potassium tert-butoxide.   The process according to claim 1, wherein the solvent in step (c) is an aprotic solvent.   12. A process according to claim 11 wherein the aprotic solvent is N-methylpyrrolidinone.   The process according to claim 11, wherein the aprotic solvent is N, N-dimethylformamide.   The method according to claim 11, wherein the aprotic solvent is dimethylacetamide.   The process of claim 1 wherein the reaction temperature is from about -5C to about 40C.   The process of claim 1, wherein the reaction temperature is from about 0C to about 25C.   The process of claim 1 wherein the base is present in an amount of about 1 mole to about 10 moles based on the compound of formula I.   The process of claim 1 wherein the base is present in an amount of about 3 moles to about 6 moles based on the compound of formula I.   The method of claim 1, wherein the contacting in step (d) is performed by means of static mixing.   The process according to claim 1, wherein the contacting in step (d) is carried out by means of a continuous reactor.   The process according to claim 1, wherein the contacting in step (d) is carried out in a batch reactor. The process of claim 1 wherein R and R ₁ are hydrogen and R ₂ is methyl. The process according to claim _1, wherein R ₁ and R ₂ together with the carbon atoms bonded to them form a benzene ring. (A) Hydroxylamine-O-sulfonic acid and Formula I in a suitable organic solvent:

A solution of the compound of
(B) preparing a suitable base solution in a suitable organic solvent;
(C) contacting the solution from step (a) and the solution from step (b) simultaneously and in a balanced amount at a suitable reaction temperature to obtain a compound of formula (II) in high purity and high yield;
Comprising the steps of formula II:

A method for producing the compound.
In the above formula,
R is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or fluoroalkyl of formula C _n H _x F _y or fluoroalkoxy of formula OC _n H _x F _y , where n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1;
R ₁ and R ₂ are the same or different and each is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or a fluoroalkyl of formula C _n H _x F _y or formula OC _n H _x F _y independently selected from fluoroalkoxy, where n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and x and The sum of y is 2n + 1 or R ₁ and R ₂ together with the carbon atoms attached to them form a C ₅ -C ₈ cyclic ring and m is 1 or 2. A solution of hydroxylamine-O-sulfonic acid in a suitable organic solvent and a suitable base solution in a suitable organic solvent can be prepared by formula I:

Is added simultaneously and in balanced amounts to a solution of the compound of formula (I), wherein the compound of formula (I) is contained in a suitable reaction vessel and is of formula (II):

A step of obtaining a compound of formula (II) in a reaction vessel and a compound of formula (III):

Reacting with a compound of to obtain a compound of formula (IV),
Including formula IV:

A method for producing the compound.
In the above formula,
R is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or fluoroalkyl of formula C _n H _x F _y or fluoroalkoxy of formula OC _n H _x F _y , where n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1;
R ₁ and R ₂ are the same or different and each is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or a fluoroalkyl of formula C _n H _x F _y or formula OC _n H _x F _y independently selected from fluoroalkoxy, where n is an integer from 1 to 4;
x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1;
R ₃ and R ₄ are the same or different and each is independently selected from hydrogen or C ₁ -C ₄ -alkyl and m is 1 or 2.   26. The method of claim 25, wherein the solvent is an aprotic solvent.   27. The method of claim 26, wherein the aprotic solvent is N-methylpyrrolidinone.   27. The method of claim 26, wherein the aprotic solvent is N, N-dimethylformamide.   27. The method of claim 26, wherein the aprotic solvent is N, N-dimethylacetamide.   26. A method according to claim 25, wherein the base is an organic base.   The process according to claim 30, wherein the organic base is an alkali metal alkoxide.   Alkali metal alkoxide is lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium 32. A method according to claim 31 selected from the group consisting of isopropoxide, potassium tert-butoxide, cesium methoxide, cesium ethoxide, cesium isopropoxide and cesium tert-butoxide.   32. The method of claim 31, wherein the alkali metal alkoxide is potassium tert-butoxide.   The process of claim 25, wherein the reaction temperature is from about -5C to about 40C.   The process of claim 25, wherein the reaction temperature is from about 0C to about 25C.   26. The method of claim 25, wherein the base is present in an amount of about 1 mole to about 10 moles based on the compound of formula I.   26. The method of claim 25, wherein the base is present in an amount of about 3 moles to about 6 moles based on the compound of formula I. R, R ₁ and R ₄ are hydrogen, R ₂ is methyl, and A method according to claim 25 R ₃ is ethyl. (A) A hydroxylamine-O-sulfonic acid solution in a suitable organic solvent and a suitable base solution in a suitable organic solvent are prepared according to Formula I:

Is added simultaneously and in balanced amounts to a solution of the compound of formula (I), wherein the compound of formula (I) is contained in a suitable reaction vessel and is of formula (II):

And the compound of formula (II) in this reaction vessel is converted to formula (III):

Is reacted with a compound of formula (IV):

Obtaining a compound of:
(B) reacting a compound of formula (IV) with a suitable reducing agent to give a compound of formula (V):

Obtaining a compound of:
(C) converting the compound of formula (V) to formula (VII) in the presence of a suitable base in a suitable organic solvent.
:

Reacting with a compound of formula (VI) and optionally reacting the compound with a suitable inorganic acid to obtain a salt of the compound of formula (VI),
Including the formula VI:

Or a suitable salt thereof.
In the above formula,
R is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or fluoroalkyl of formula C _n H _x F _y or fluoroalkoxy of formula OC _n H _x F _y , where n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1;
R ₁ and R ₂ are the same or different and each is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or a fluoroalkyl of formula C _n H _x F _y or formula OC _n H _x F _y independently selected from fluoroalkoxy, where n is an integer from 1 to 4;
x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1;
R ₃ and R ₄ are the same or different and each is independently selected from hydrogen or C ₁ -C ₄ -alkyl and m is 1 or 2;
R ₅ is hydrogen, nitro, amino, halogen, C _1-4 -alkyl, C _1-4 -alkanoylamino, phenyl-C _1-4 -alkanoylamino, phenylcarbonylamino, alkylamino or phenyl-C _1-4 -Alkylamino,
X is a halogen,
m and n are 1 or 2, and p is 0 or 1.   40. The method of claim 39, wherein the reducing agent in step (b) is sodium borohydride.   40. The method of claim 39, wherein the reaction in step (b) is carried out in a suitable organic solvent.   42. The method of claim 41, wherein the solvent is an aprotic polar solvent. 42. The method of claim 41, wherein the solvent is N-methylpyrrolidinone, N, N-dimethylformamide, dimethylacetamide, tetrahydrofuran, heptane, hexane, toluene, petroleum ether or mixtures thereof.   42. The method of claim 41, wherein the solvent is N-methylpyrrolidinone or a mixture of N-methylpyrrolidinone and n-heptane.   40. The method of claim 39, wherein the reaction temperature in step (a) is in the range of about -70C to about 150C.   40. The method of claim 39, wherein the reaction temperature in step (a) is in the range of about -20C to about 15C.   40. The method of claim 39, wherein the base in step (c) is potassium tert-butoxide.   40. The method of claim 39, wherein step (c) is performed by means of a static mixer.   40. The method of claim 39, wherein step (c) is performed in a continuous stirred tank reactor.   40. The method of claim 39, wherein step (c) is performed in a batch reactor.   40. The method of claim 39, wherein step (c) is performed in a microreactor.   40. The method of claim 39, wherein step (c) is performed in a continuous stirred tank reactor combined with a loop system static mixer. Formula (IV):

Wherein R is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or fluoroalkyl of formula C _n H _x F _y or fluoroalkoxy of formula OC _n H _x F _y Where n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1;
R ₁ and R ₂ are the same or different and each is hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, benzyloxy or a fluoroalkyl of formula C _n H _x F _y or formula OC _n H _x F _y independently selected from fluoroalkoxy, where n is an integer from 1 to 4;
x is an integer from 0 to 8, y is an integer from 1 to 9, and the sum of x and y is 2n + 1, or R ₁ and R ₂ are taken together with the carbon atom attached to them. C ₅ -C ₈ cyclic ring to form Te,
R ₃ and R ₄ are the same or different and each is independently selected from hydrogen or C ₁ -C ₄ -alkyl and m is 1 or 2;
Provided that when R and R ₃ are hydrogen, R ₄ is not hydrogen or methyl.]
Or an enantiomer thereof, a stereoisomer thereof or a mixture thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a derivative thereof. R, R ₁ and R ₃ are hydrogen, and the compound of Claim 53 R ₂ is methyl. 3-methyl-N- (propylidene) -1H-indole-1-amine,
N- (propylidene) -1H-indole-1-amine,
5-benzyloxy-N- (propylidene) -1H-indole-1-amine,
54. The compound of claim 53, selected from the group consisting of 5-methoxy-N- (propylidene) -1H-indole-1-amine, and N- (propylidene) -1H-carbazol-1-amine.